A Molecular Perspective on Mitochondrial Membrane Fusion: From the Key Players to Oligomerization and Tethering of Mitofusin

Abstract

Mitochondria are dynamic organelles characterized by an ultrastructural organization which is essential in maintaining their quality control and ensure functional efficiency. The complex mitochondrial network is the result of the two ongoing forces of fusion and fission of inner and outer membranes. Understanding the functional details of mitochondrial dynamics is physiologically relevant as perturbations of this delicate equilibrium have critical consequences and involved in several neurological disorders. Molecular actors involved in this process are large GTPases from the dynamin-related protein family. They catalyze nucleotide-dependent membrane remodeling and are widely conserved from bacteria to higher eukaryotes. Although structural characterization of different family members has contributed to understand molecular mechanisms of mitochondrial dynamics in more detail, the complete structure of some members as well as the precise assembly of functional oligomers remain largely unknown. As increasing structural data becomes available, the domain modularity across the dynamin superfamily emerged as a foundation for transfer the knowledge towards less characterized members. In this review we will first provide an overview of the main actors involved in mitochondrial dynamics. We then discuss recent example of computational methodologies for the study of mitofusin oligomers, and present how the usage of integrative modeling in conjunction with biochemical data can be an asset in progress the still challenging field of membrane dynamics.

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

“…Interestingly, these regions map to mutations associated with CMT2A [204], suggesting pathogenic relevance. Their importance as a driving force for membrane merging could be confirmed with subsequent functional analysis, allowing further dissection of the fusion mechanism [75,76,194,195,[205][206][207][208][209][210][211][212]. Consistent with the self-assembly properties of DRPs, mitofusins can be found in multiple oligomerization states [184,207] (Figure 4C).…”

“…Interestingly, these regions map to mutations associated with CMT2A [ 204 ], suggesting pathogenic relevance. Their importance as a driving force for membrane merging could be confirmed with subsequent functional analysis, allowing further dissection of the fusion mechanism [ 75 , 76 , 194 , 195 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 ].…”

“…Subsequently, mitofusins undergo higher oligomerization [ 211 , 216 ]. Several possible assembly models have been proposed [ 207 , 208 , 209 ], likely involving interaction via the G–G interface and intermolecular hydrophobic interactions between the HR2 domains [ 195 , 217 , 218 ]. Although the exact triggers facilitating trans oligomerization are unknown, studies in mammals suggest that cytosolic signaling regulates Mfn2 oligomerization, e.g., via the oxidative state and the apoptosis regulator BAX [ 197 , 212 , 219 , 220 ].…”

Mitochondrial Dynamics, Mitophagy, and Mitochondria–Endoplasmic Reticulum Contact Sites Crosstalk Under Hypoxia

“…Previously, the functional overlap was demonstrated between MFN1 and MFN2 in mitochondrial fusion, and structural and functional similarities between them enabled partial compensation for the loss of each other (Detmer and Chan 2007). Furthermore, MFN1 and MFN2 have been reported to share a high degree of homology and sequence similarity (De Vecchis et al, 2019). Following the OMM fusion, the IMM fusion is governed by OPA1 (Figure 1C).…”

Special Issue: Membrane and Receptor Dynamics

“…Taly and co-workers have recently used molecular modeling approaches to analyze the determinants of membrane curvature and the first steps of mitochondrial fusion. They report here a general model using data from experimental and computational methods to explain our current understanding of membrane fusion events (De Vecchis et al 2019). Membrane fission is an emerging area where mechanical properties of the membrane are intricately balanced to signaling pathways and endocytotic machineries.…”